UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Modeling human gene variants that affect WNT signalling in the chicken embryo Gignac, Sarah J.


The study of rare genetic diseases provides valuable insights into human gene function. The chicken embryo was used as a model to investigate the role of WNT signaling in skeletogenesis and to elucidate the functional consequences of mutations in dominant Robinow Syndrome (RS). RS mutations affect non-canonical WNT signaling that controls a variety of developmental events to regulate convergent extension, cell polarity, and cytoskeletal rearrangement. RS is characterized by short stature, mesomelic limb shortening, hypertelorism, and mandibular hypoplasia. Mutations in dominant RS occur in several components of the non-canonical WNT signaling pathway, and this study is focusing on two mutations in WNT5A ligand (WNT family member) and three mutations in Dishevelled1 (DVL1), a protein that relays WNT signals intracellularly. We delivered the human genes to the chicken embryo using replication competent retroviruses (RCAS) and analyzed morphologic, cellular, and molecular effects in the forelimbs and mandible. Misexpression of mutants in dominant RS led to a shortening of the forelimb and mandible and caused polarity disruptions in the chondrocytes that were not seen in the GFP virus controls. The variants were unable to activate canonical WNT signaling and over-activated non-canonical WNT signaling, demonstrating the importance of non-canonical WNT signaling in skeletogenesis. Dominant RS mutations have dominant neomorphic effects on chondrogenesis that interfere with the function of the wild-type protein. This work establishes that the dominant effect of the mutations leads to elevated non-canonical WNT signaling and randomizes the distribution of planar cell polarity molecules of which produces shortened skeletal elements.

Item Media

Item Citations and Data


Attribution-NonCommercial-NoDerivatives 4.0 International